Islet T cells secreting IFN-gamma in NOD mouse diabetes: arrest by p277 peptide treatment.
Non-obese diabetic (NOD) mice spontaneously develop insulin-dependent (type 1) diabetes mellitus (IDDM) caused by T cells which destroy the insulin-producing islet beta-cells. Since cytokines are involved in this auto-immune beta-cell damage, we used an ELISPOT assay to enumerate the islet-associated T cells that secreted interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha) or interleukin-4 (IL-4). We used mitogenic anti-CD3 antibody to activate all the T cells capable of responding, irrespective of their antigen specificity. We found that NOD females, more susceptible than males to IDDM, accumulated islet IFN-gamma producers more rapidly with age than did the males. Acceleration of male IDDM by cyclophosphamide led to a marked increase in IFN-gamma secreting islet T cells. In contrast, a decrease in IFN-gamma-producing islet T cells was associated with arrest of IDDM by administration of peptide p277 of the 60 kDa heat-shock protein (hsp60) to 12-week-old female NOD mice. The p277-treated mice later manifested a greater number of islets and fewer leukocytes per islet than did the mice treated with a bacterial hsp60 peptide. Thus, the development of diabetes could be correlated with the accumulation in the islets of T cells producing IFN-gamma, and destructive insulitis could be downregulated by the administration of a single peptide.
Ablamunits
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Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel.
Elias
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Reshef
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Cohen
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IR
D000367:Age Factors; D000595:Amino Acid Sequence; D000818:Animals; D002138:Calibration; D018834:Chaperonin 60; D003520:Cyclophosphamide / Q000494:pharmacology; D016207:Cytokines / Q000096:biosynthesis; D003922:Diabetes Mellitus, Type 1 / Q000209:etiology / Q000276:immunology / Q000628:therapy*; D004797:Enzyme-Linked Immunosorbent Assay / Q000592:standards; D005260:Female; D006360:Heat-Shock Proteins / Q000627:therapeutic use*; D007369:Interferon Inducers / Q000494:pharmacology; D007371:Interferon-gamma / Q000187:drug effects / Q000378:metabolism*; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000627:therapeutic use*; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology
D018834:Chaperonin 60; D016207:Cytokines; D006360:Heat-Shock Proteins; D007369:Interferon Inducers; D010446:Peptide Fragments; C095402:peptide 277, heat shock protein 60; D007371:Interferon-gamma; D003520:Cyclophosphamide